The term Glaucoma describes a group of ocular disorders with optic nerve damage in the region of the optic nerve head. This is usually associated with intraocular pressure levels above the statistically normal range. Glaucoma of all types is the second leading cause of blindness in the USA, accounting for 11% of all blind registrations. It is the major cause of blindness in African Americans. In England and Wales glaucoma is the cause, or a contributory cause, of 13% of the registered blind. The chronic insidious type, Primary Open Angel Glaucoma (POAG) has a prevalence of about 1% of a predominantly white population over 40 years of age. The prevalence is 4 times higher in people of African origin. POAG accounts for 60% of all cases and 78% of the blindness caused by glaucoma. There is accumulating evidence that genetic predisposition is a major factor in the development of this condition. Accordingly, we are proposing to identity and characterize the genetic factors underlying the autosomal dominant form of POAG by genetic linkage analysis and positional mapping. We have ascertained multi-generational families by adopting very restrictive diagnostic criteria. Segregation analyses on a group of 57 pedigrees showed that POAG is inherited as an autosomal dominant trait. A total of 85 meioses in 17 pedigrees are being used as our initial screening panel with selected markers. POWER analysis indicated that even if we exclude all the unaffected members from our screening panel (on average aged 50.4), the affected meioses alone have sufficient power to detect linkage with any marker. We have so far excluded genetic linkage of POAG to the following markers: Collagen (types 1A1,1A2,3A1/5A2), Elastin, Thrombospondin, Sprectrin, Crystalline, Paired Box Homeotic Gene 3 (PAX3), Alkaline Phosphatase (ALPP), D7S440, D21s17` and Fibrillin-5. We are proposing to study the genetic linkage relationship of POAG to other genes including Collagen (type 4A1,4A2,5A1), Laminin, Tubulin, Actin, Ankyrin, Vimentin and Fibronectin. If linkage to the POAG locus is not proven, we will continue our genotyping with a series of other genes and, if necessary proceed with other random DNA markers (VNDRs, VNTRs, RFLPs). This process will continue until linkage with POAG is proven and possibility of genetic heterogeneity is explored. The long term objective of this proposal is the identification of a biological marker that can be used for the early diagnosis of individuals at risk. The mapping of POAG will be the first critical step preceding cloning of the gene and identification of individual mutations. This may eventually facilitate a full understanding of the embryology and function of the human eye.